Abstract
Retinitis pigmentosa (RP) is an inherited retinal disease (IRD) with an overall prevalence of 1 in 4000 individuals. Mutations in EYS (Eyes shut homolog) are among the most frequent causes of non-syndromic autosomal recessively inherited RP and act via a loss-of-function mechanism. In light of the recent successes for other IRDs, we investigated the therapeutic potential of exon skipping for EYS-associated RP. CRISPR/Cas9 was employed to generate zebrafish from which the region encompassing the orthologous exons 37-41 of human EYS (eys exons 40-44) was excised from the genome. The excision of these exons was predicted to maintain the open reading frame and to result in the removal of exactly one Laminin G and two EGF domains. Although the eysΔexon40-44 transcript was found at levels comparable to wild-type eys, and no unwanted off-target modifications were identified within the eys coding sequence after single-molecule sequencing, EysΔexon40-44 protein expression could not be detected. Visual motor response experiments revealed that eysΔexon40-44 larvae were visually impaired and histological analysis revealed a progressive degeneration of the retinal outer nuclear layer in these zebrafish. Altogether, the data obtained in our zebrafish model currently provide no indications for the skipping of EYS exons 37-41 as an effective future treatment strategy for EYS-associated RP.
Highlights
IntroductionRetinitis pigmentosa (RP) is an inherited retinal disease (IRD) with an overall prevalence of 1 in 4000 individuals, affecting almost 2 million individuals worldwide [1,2]
To identify a potential target region to assess the therapeutic potential of exon skipping as a future treatment option, the conservation of the Eyes shut homolog (EYS) exon structure and protein domain architecture between human and zebrafish was analyzed (Figure 1)
Discussion counting for approximately 5-35% of all arRP cases in the European and Asian populations order to investigate the therapeutic potential of exon skipping for the Mutations in EYSInare among the most frequent causes of non-syndromic arRP, accounting future treatment of EYS-associated andAsian characterized a stable zebrafish for approximately of all arRP casesRP, in we the generated
Summary
Retinitis pigmentosa (RP) is an inherited retinal disease (IRD) with an overall prevalence of 1 in 4000 individuals, affecting almost 2 million individuals worldwide [1,2]. Patients present with a progressive loss of visual function caused by the degeneration of the light-sensitive photoreceptor cells in the retina, often resulting in total blindness in the fifth or sixth decade of life. RP typically manifests with night blindness and visual field constriction from early adolescence onwards, followed by a gradual decrease of visual acuity later in life. This non-congenital onset and slowly progressive nature of RP provides ample time for therapeutic intervention
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
